1. Technical Field
The invention relates to 4-substituted-2-amino-pyrimidine compounds, compositions comprising such compounds, methods for making the compounds, and methods of treating conditions and disorders using such compounds and compositions.
2. Description of Related Technology
Histamine is a well-known modulator of neuronal activity. At least four types of histamine receptors have been reported in the literature, typically referred to as histamine-1, histamine-2, histamine-3, and histamine-4. The class of histamine receptor known as histamine-3 receptors is believed to play a role in neurotransmission in the central nervous system.
The histamine-3 (H3) receptor was first characterized pharmacologically on histaminergic nerve terminals (Nature 1983, 302, 832-837), where it regulates the release of neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs, cardiovascular system and gastrointestinal tract. H3 receptors are thought to be disposed presynaptically on histaminergic nerve endings, and also on neurons possessing other activity, such as adrenergic, cholinergic, serotoninergic, and dopaminergic activity. The existence of H3 receptors has been confirmed by the development of selective H3 receptor agonists and antagonists (Nature 1987, 327, 117-123; Leurs and Timmerman, ed. “The History of H3 Receptor: a Target for New Drugs,” Elsevier, 1998). The activity at the H3 receptors can be modified or regulated by the administration of H3 receptor ligands. The ligands can demonstrate agonist, partial agonist, antagonist, or inverse agonist activity. Activation of presynaptic H3 receptors by full or partial agonists suppresses the release of the neurotransmitter associated with these neurons. Conversely, blockade of presynaptic H3 receptors by antagonists or inverse agonists enhances the release of the neurotransmitter associated with these neurons.
Therapeutic potential for H3 receptor agonists has been proposed for conditions and disorders related to a) neurological processes, such as sleep disorders (Neuropsychopharmacology 1996, 15(1), 31-35), migraine (European Journal of Pharmacology 1992, 224, 145-150), pain (Journal of Pharmacology and Experimental Therapeutics 2000, 295, 219-225), and Alzheimer's disease (Journal of Neurochemistry 2007, 103(1), 248-258); b) cardiovascular function, such as arrhythmias and myocardial infarction (WO2002/064212A1); c) inflammatory processes, such as edema, plasma protein extravasation, and polymorphonuclear leukocyte infiltration (Journal of Pharmacology and Experimental Therapeutics 2000, 295, 219-225); and d) gastrointestinal function, such as gastric acid related diseases (Digestive Diseases and Sciences 1995, 40(9), 2052-2063).
Several H3 receptor agonists have been reported, such as R-alpha-methyl-histamine (Nature 1987, 327, 117-123), R-alpha-S-beta-dimethyl-histamine (Journal of Medicinal Chemistry 1992, 35(23), 4434-4441), imetit (Journal of Pharmacology and Experimental Therapeutics 1992, 263, 304-310), immepip (Journal of Medicinal Chemistry 1994, 37(3), 332-333), Sch-50971 (Bioorganic & Medicinal Chemistry Letters 1998, 8, 243-248), imifuramine (Tetrahedron Letters 1999, 40, 2561-2564), and immethridine (Journal of Medicinal Chemistry 2004, 47(10), 2414-2417), however, all of these compounds contain an imidazole ring in their structures. Imidazole moieties have been reported to impair the drug-likeness of compounds. Imidazole-containing H3 ligands have been reported to have poor ability to access the central nervous system (CNS) (Ganellin, et al. Arch. Pharm. Pharm. Med. Chem. 1998, page 395). Since H3 receptors are predominantly found in the CNS and the diseases targeted for treatment are modulated by neuronal tissues, it would be beneficial to provide non-imidazole containing CNS ligands. Compounds with imidazole moieties are usually potent inhibitors of liver enzymes, particularly the cytochrome P450 enzymes that metabolize co-administered drugs. Literature reports of imidazole-containing H3 ligands can be found in a) LaBella, F. S.; Queen, G.; Glavin, G.; Durant, G.; Stein, D.; Brandes, L. J. The H3 antagonist thioperamide inhibits adrenal steroidogenesis and histamine binding to adrenocortical microsomes and inhibits cytochrome P450. Br. J. Pharmacol. 1992, 107, 161-164, b) Yang, R.; Hey, J. A.; Aslanian, R.; Rizzo, C. A. Coordination of histamine H3-receptor antagonists with human adrenal cytochrome P450 enzymes. Pharmacology 2002, 66, 128-135, c) Harper, E. A.; Shankley, N. P.; Black, J. W. Characterization of the binding of [3H]-clobenpropit to histamine H3-receptors in guinea pig cerebral cortex membranes. Br. J. Pharmacol. 1999, 128, 881-890.
An attempt to overcome some of the deficiencies of an imidazole-based H3 receptor agonist is exemplified by BP 2-94, a benzophenone-imine prodrug of R-alpha-methyl-histamine (Journal of Pharmacology and Experimental Therapeutics 1997, 281, 1085-1094). Although this prodrug did address the rapid metabolism of R-alpha-methyl-histamine in humans and succeeded in providing significant levels in plasma and in peripheral tissues, it failed to deliver significant brain levels or address cytochrome P450-based drug interactions.
Only a very few non-imidazole structures have ever been reported to be H3 receptor agonists, such as three spiroindolinone natural products (Journal of Antibiotics 2007, 60(11), 667-673), however, these compounds lack good drug-like properties (Gilbert M. Rishton. Nonleadlikeness and leadlikeness in biochemical screening. Drug Discovery Today 2003, 8(2), 86) since their molecular weights are greater than 500 and they contain potential chemically reactive functional groups such as an ester, an aldehyde, and an epoxide. Another class of non-imidazole structures, derivatives of the sesquiterpene α-cedrene, have been described as H3 receptor agonists (JP6345642A), however, the data described also reported that these have very low potency (EC50>10 μM). It would be beneficial to provide additional non-imidazole compounds with improved drug-like properties and potency, demonstrating full or partial agonist activity at H3 receptors that can be incorporated into pharmaceutical compositions useful for therapeutic methods.